Upsurge of renewed interest in the use of HRT among post-menopausal women in the light of revised global consensus statement

Menopause is that time in the reproductive phase of a woman where by the levels of circulating estrogen diminishes to such low levels as to cause physical, psychological and sexual disturbances. At or around menopause (between 48 to 52 years) there is a decline in the ovarian functions and in the amounts of hormones produced by hypothalamus-FSH and LH which results in decrease in the ovarian hormones. While cessation of periods can be welcome to many a women, the wide ranging effects of lack of estrogen can be discomforting to an equal many. One alternative to overcome the hazards of menopausal syndrome is the use of Hormone Replacement Therapy (HRT).

Many trials on the use of hormone replacement therapy during the past two decades have provided contradictory results on its risks and benefits in post-menopausal women that has consequently put the medical community in quandary in decision making about use of HRT. The use of HRT declined globally following publication of the first data from the Women’s Health Initiative (WHI) trial in 2002, with the revelation that there was an increased risk of breast cancer and coronary heart disease (CHD) in postmenopausal women taking HRT. Following this, Heart and Estrogen/Progestin Replacement Study & its follow-up (HERS I & II), WHI Memory Study (WHIMS), Women’s international study of long duration oestrogen after menopause (WISDOM) and the Million Women Study (MWS) published results that were consistent with the findings of the WHI study. This reduced enthusiasm for HRT use, and many health professionals and patients considered the use of such hormones as ‘unsafe’, leading to reduction in HRT prescribing¹.

However, recent publications from the International Menopause Society^13,14 indicate that HRT is the first-line and most effective treatment for menopausal symptoms.  Moreover when the full results of the WHI trial were subsequently published it appeared that HRT may confer benefit for CHD prevention below age 60. The 2013 British Menopause Society & Women’s Health Concern recommendations² on hormone replacement therapy and European guidance³ for the diagnosis and management of osteoporosis in postmenopausal women published in 2013 also supported this opinion. These revelations renew interest in realms of HRT use among post-menopausal women.

The differences in age at initiation and the duration of HRT are key points. The intention dose and regimen of HRT need to be individualized based on the principle of choosing the lowest appropriate dose in relation to the severity of the symptoms and the time and age. HRT appears to decrease coronary artery disease in younger women, near menopause yet, in older women, HRT increases risks of coronary event. New findings also showed that the additional benefits of HRT use for those initiating HRT in the 50-59 age group, or for those less than 10 years past the menopause – trends to a lower risk from heart disease; a lower risk of death from any cause; no clear increased risk from stroke. They also showed a general increased risk for those starting HRT after the age of 60⁴. This article reviews the current body of evidence on HRT use among post-menopausal women in light of the consensus statement published by International Menopause Society in 2013 and revised recently in 2016.

In 1975, estrogen only was found to be associated with an increased risk of endometrial cancer. In November 2015, NICE guidelines on hormone therapy were published that did not take this risk into account. A systematic literature review of 28 published studies assessing the safety of estrogen plus progestin therapy according to the risk of endometrial cancer, while considering both regimen and type of progestin concluded that use of unopposed estrogen, tibolone and sequential combined therapy increases the risk of endometrial cancer. Continuous combined therapy might provide a lower risk than never use, even when treatment lasts less than 5 years, and therapy for more than 10 years does not increase risk; micronized progesterone increases the risk of endometrial cancer, regardless of regimen⁵.

Global consensus statement on menopausal hormone therapy

The past one and a half decade has witnessed much confusion regarding the use of menopausal hormone therapy (MHT). New evidence challenged previously accepted clinical guidelines, especially on aspects of safety and disease prevention. This led to many women unnecessarily being denied the use of MHT. Detailed revised guidelines were published and regularly updated by the major regional menopause societies. The confusion was initially escalated by significant differences amongst published guidelines. In recent revisions, the differences have become much less. In view of this, The International Menopause Society (IMS) took the initiative to arrange a round-table discussion, in November 2012, between representatives of the major regional menopause societies to reach consensus on core recommendations regarding MHT. The aim was to produce a short document, only containing the points of consensus. It is acknowledged that, in view of the global variance of disease and regulatory restrictions, these core recommendations do not replace the more detailed and fully referenced recommendations prepared by individual national and regional societies^6,7,8,9,12. IMS document serves to emphasize international consensus regarding MHT and is aimed at empowering women and health-care practitioners in the appropriate use of MHT. The publication of the Global Consensus on Menopausal Hormone Therapy in 2013^10,11 by leading global menopause societies succeeded in presenting guidelines in a troubled therapeutic area that are helpful to both health-care providers and potential users of menopausal hormone therapy.

In June, 2016, a Revised Global Consensus Statement on menopausal hormone therapy^13,14 has been endorsed by The International Menopause Society, The North American Menopause Society, The Endocrine Society, The European Menopause and Andropause Society, The Asia Pacific Menopause Federation, The International Osteoporosis Foundation and The Federation of Latin American Menopause Societies. This statement has been simultaneously published in the journals Climacteric and Maturitas, on behalf of the International Menopause Society and The European Menopause and Andropause Society, respectively. Statement reads as under:

The revised statement aims at updating and expanding the areas of consensus. The revised statement contains only areas of consensus and does not replace the more detailed and fully referenced recommendations of the individual societies. This statement is expected to enable health-care providers to offer those women in midlife, who may benefit from MHT, the opportunity to make an informed decision.

Benefit/risk profile of MHT^13,14

MHT, including tibolone and the combination of conjugated equine estrogens and bazedoxifene (CE/BZA), is the most effective treatment for vasomotor symptoms (VMS) associated with menopause at any age, but benefits are more likely to outweigh risks if initiated for symptomatic women before the age of 60 years or within 10 years after menopause.

If MHT is contraindicated or not desired for treatment of VMS, selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors such as paroxetine, escitalopram, venlafaxine and desvenlafaxine, which have been shown to be effective in randomized controlled trials (RCTs), may be considered. Gabapentin may also be considered.

Quality of life, sexual function and other menopause-related complaints, such as joint and muscle pains, mood changes and sleep disturbances, may improve during MHT.

MHT, including tibolone and CE/BZA, is effective in the prevention of bone loss in postmenopausal women.

MHT has been shown to significantly lower the risk of hip, vertebral and other osteoporosis-related fractures in postmenopausal women.

MHT is the only therapy available with RCT-proven efficacy of fracture reduction in a group of postmenopausal women not selected for being at risk of fracture and with mean T-scores in the normal to osteopenic range.

MHT, including tibolone, can be initiated in postmenopausal women at risk of fracture or osteoporosis before the age of 60 years or within 10 years after menopause.

Initiation of MHT after the age of 60 years for the indication of fracture prevention is considered second-line therapy and requires individually calculated benefit/risk, compared to other approved drugs. If MHT is elected, the lowest effective dose should be used.

MHT, including tibolone, is effective in the treatment of vulvovaginal atrophy (VVA), now also considered as a component of the genitourinary syndrome of menopause (GSM). Local low-dose estrogen therapy is preferred for women whose symptoms are limited to vaginal dryness or associated discomfort with intercourse or for the prevention of recurrent urinary tract infections. Ospemifene, an oral selective estrogen receptor modulator, is also licensed in some countries for the treatment of dyspareunia attributed to VVA.

RCTs and observational data as well as meta-analyses provide evidence that standard-dose estrogen-alone MHT may decrease the risk of myocardial infarction and all-cause mortality when initiated in women younger than 60 years of age and/or within 10 years of menopause.

Data on estrogen plus progestogen MHT initiated in women younger than age 60 years or within 10 years of menopause show a less compelling trend for mortality benefit, and evidence on cardioprotection is less robust with inconsistent results compared to the estrogen-alone group.

The risk of venous thromboembolism (VTE) and ischemic stroke increases with oral MHT, although the absolute risk of stroke with initiation of MHT before age 60 years is rare. Observational studies and a meta-analysis point to a probable lower risk of VTE and possibly stroke with transdermal therapy (0.05 mg twice weekly or lower) compared to oral therapy.

The risk of breast cancer in women over 50 years of age associated with MHT is a complex issue with decreased risk reported from RCTs for estrogen alone (CE in the Women's Health Initiative (WHI)) in women with hysterectomy and a possible increased risk when combined with a progestin (medroxyprogesterone acetate in the WHI) in women without hysterectomy. The increased risk of breast cancer thus seems to be primarily, but not exclusively, associated with the use of a progestin with estrogen therapy in women without hysterectomy and may be related to the duration of use.

The risk of breast cancer attributable to MHT is rare. It equates to an incidence of women experiencing a spontaneous or iatrogenic menopause before the age of 45 years and particularly before 40 years are at a higher risk for cardiovascular disease and osteoporosis and may be at increased risk of affective disorders and dementia. In such women, MHT reduces symptoms and preserves bone density. Observational studies that suggest MHT is associated with reduced risk of heart disease, longer lifespan, and reduced risk of dementia require confirmation in RCTs. MHT is advised at least until the average age of menopause.

MHT initiated in early menopause has no substantial effect on cognition, but, based on observational studies, it may prevent Alzheimer’s disease in later life. In RCTs, oral MHT initiated in women aged 65 or older also has no substantial effect on cognition and increases the risk of dementia.

MHT may be beneficial in improving mood in early postmenopausal women with depressive and/or anxiety symptoms. MHT may also be beneficial for perimenopausal women with major depression but antidepressant therapy remains first-line treatment in this setting.

General principles governing the use of MHT^13,14

The option of MHT is an individual decision in terms of quality of life and health priorities as well as personal risk factors such as age, time since menopause and the risk of VTE, stroke, ischemic heart disease and breast cancer. MHT should not be recommended without a clear indication for its use.

Consideration of MHT for symptom relief or osteoporosis prevention should be a part of an overall strategy including lifestyle recommendations regarding diet, exercise, smoking cessation and safe levels of alcohol consumption for maintaining the health and quality of life of peri- and postmenopausal women.

MHT includes a wide range of hormonal products and routes of administration, including tibolone (where available) or CE/BZA, with potentially different risks and benefits. However, evidence regarding differences in risks and benefits between different products is limited.

The type and route of administration of MHT should be consistent with treatment goals, patient preference and safety issues and should be individualized. The dosage should be titrated to the lowest appropriate and most effective dose.

Duration of treatment should be consistent with the treatment goals of the individual, and the benefit/risk profile needs to be individually reassessed annually. This is important in view of new data indicating longer duration of VMS in some women.

Estrogen as a single systemic agent is appropriate in women after hysterectomy but concomitant progestogen is required in the presence of a uterus for endometrial protection with the exception that CE can be combined with BZA for uterine protection.

The use of continuous testosterone therapy, either alone or with MHT, is supported in carefully selected postmenopausal women with sexual interest/arousal disorder (in countries with regulatory approval).

The use of custom-compounded hormone therapy is not recommended because of lack of regulation, rigorous safety and efficacy testing, batch standardization, and purity measures.

Current safety data do not support the use of systemic MHT in breast cancer survivors, although discussions, in selected women and in conjunction with each woman’s oncologist, may occur for compelling reasons after non-hormonal or complementary options have been unsuccessful.

On continuing use of systemic hormone therapy after age 65, The North American Menopause Society Statement has provided that if a woman has been advised of the increase in risks associated with continuing HT beyond age 60 and has clinical supervision, extending HT use with the lowest effective dose is acceptable under some circumstances, such as for the woman who has persistent bothersome menopausal symptoms and for whom her clinician has determined that the benefits of menopause symptom relief outweigh the risks. Use of HT should be individualized and not discontinued solely based on a woman’s age. The decision to continue or discontinue HT should be made jointly by the woman and her healthcare provider¹⁵.

Conclusion

Body of evidence on HRT use suggests that all interventions to relieve menopausal symptoms should be individually tailored to the specific needs and concerns of each woman to provide an optimal quality of life. Menopause – the natural event in every woman’s life should be treated keeping in view the symptoms experienced by many women in milder or severe form. For relief of hot flushes and vaginal dryness HRT remains the most effective pharmacologic intervention. The benefits of HRT include protection from osteoporotic fracture and colon cancer but evidences show that the risk of CHD is reduced in younger women (less than 60 years) and women beginning  HRT near menopause (within 10 years). HRT for the treatment of menopausal symptoms and prevention of osteoporosis is suggestive because studies support that estrogens and estrogen plus progestins increase bone density and reduce risk of fractures by preventing bone loss in both young and older postmenopausal women. The decision to use HRT should be a joint one between a woman and her doctor with consideration to her need for treatment, her age, history, risk factors and personal preferences. For all women the lowest effective dose should be used for the shortest time. The need to continue the HRT should be reviewed every 6 to 12 months taking into consideration the change risk-benefit balance. Recent literature review suggests that the use of HRT in management of menopause in specific age groups, regimens, dosage forms is safe as the benefits in such patterns outweigh the risks associated with the HRT usage.

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